(a) Field of the Invention
This invention relates to arylxanthines which are relatively potent adenosine receptor antagonists with enhanced water solubility and beneficial pharmacological activity. The are 1,3-alkyl-substituted-8-(3,4-,3- or 4-substituted phenyl) xanthines and the pharmaceutically acceptable salts thereof.
(b) State of the Art
Xanthines of various types have been used or proposed as drugs for various indications. For example theophylline and aminophylline relax the smooth muscle of the bronchial airways and pulmonary blood vessels, thereby acting as pulmonary vasodilators, bronchodilators and smooth muscle relaxants. Like other xanthines these compounds possess the following actions as well: coronary vasodilator, diuretic, cardiac and cerebral stimulant and skeletal muscle stimulant. Dyphylline is another xanthine having activity similar to that of theophylline and aminophylline.
Adenosine is a known vasodilator, negative inotropic and chronotropic agent of the cardiovascular system. Adenosine antagonists such as aminophylline will increase cardiac output which makes them useful as cardiotonic agents. Presently, there are only weak nonselective adenosine antagonists available such as aminophylline and theophylline. The ideal cardiotonic, based on the principle of adenosine antagonism, should reverse the depressed contractility of myocardial muscle caused by endogenously released adenosine without causing an increase in heart rate or peripheral pressure. From that point of view selectivity toward the A.sub.1 --subclass of adenosine receptor is highly desired.
Presently available xanthine-derivative cardiotonics, theophylline and aminophylline, do not show any remarkable degree of selectivity. The present invention provides new, more potent, selective adenosine antagonists having physical properties, notably increased water solubility, which result in beneficial pharmacological activity.
Synthesized by Bruns et al. (Proc. Nat'l. Acad. Sci. USA, 1983, 80, 2077), 8-arylxanthines show a great increase in the affinity toward the adenosine (A.sub.1) receptor with the best compound reported in the series being: 1,3-dipropyl-8-[2-amino-4-chlorophenyl]xanthine [PACPX] (I). ##STR1## This compound was reported 70,000 times more potent [at the receptor level] than theophylline and selective toward A.sub.1 --adenosine receptor. It is also approximately 40,000 times more lipophilic. Calculation of its partition coefficient using Rekker's hydrophobic fragmental constants gives an approximate log P=4.0. That fact can be neglected in the studies using isolated receptor preparations since the compound is 70,000 times more potent. However, from the pharmacological point of view the high lipophilicity makes this compound undesirable for therapeutical use. One has to expect an extremely high CNS uptake, poor blood clearance and extensive metabolism. It has been suggested that as an apparent consequence of their extreme lipophilicity, many 8-arylxanthines, such as those disclosed in U.S. Pat. No. 4,593,095, particularly the preferred compound PACPX, demonstrate little overt activity in animals. In one test where activity is seen, The NECA depressed Langendorff heart in guinea pigs, PACPX has unfavorable force and rate properties, whereas the water soluble compounds of this invention increase the force of contraction at doses that are lower than those required.
Bruns attempted to lower the lipophilicity of 8-arylxanthines. He synthesized 8-[4-sulfophenyl]-theophylline (II). This compound was studied at the receptor level by Fredholm and Sandberg (Br. J. Pharmacol. 1983, 80, 639). ##STR2## When the above mentioned authors studied the effect of selected xanthine derivatives on the adenosine 5'-ethylcarboxamide (NECA)-induced accumulation of cyclic AMP in guinea pig thymocytes, (II) was only 3 fold less potent than 8-phenyltheophylline while lipophilicity of (II) was two orders of magnitude lower. Unfortunately, introduction of the sulfonyl group led to a decrease in selectivity [Daly et al. J. Med. Chem. 1985, 28, 487].
This invention provides a series of new 8-arylxanthines which retain most of the potency and receptor selectivity of PACPX with simultaneous decrease in the lipophilicity and which cause an increase in the force of contraction in the NECA-depressed Langendorff heart preparation in guinea pigs in doses below those that increase the rate of contraction.